The present invention relates generally to the field of health and medicine, and in particular to a new and useful spectrophotometric colorimeter methods and apparatus determine the efficacy of a drug, by measuring and storing the color of a subject's skin over time for tracking and diagnosing aspects of the subject's cardiovascular condition.
In physiology, “perfusion” is the process of a body delivering blood to capillary beds in living tissues. As more or less blood is delivered to capillaries near a skin surface, the color of the skin changes. For example, skin having more blood delivered near the surface is more red than skin on the same individual having less blood. Aspects of the work leading to this invention have determined that changes in skin color and perfusion will be greater for patients in better cardiovascular health, and smaller for patients who are not in good cardiovascular health, for a given stimulus.
Endothelium is a type of epithelium that lines the interior surface of blood vessels and lymphatic vessels. It is a thin layer of simple squamous cells called endothelial cells. Vascular endothelial cells line the entire circulatory system, from the heart to the smallest capillaries. Endothelium of the interior surfaces of the heart chambers is called endocardium. Endothelial dysfunction is linked to various vascular diseases, and is often regarded as a key early event in the development of atherosclerosis. Impaired endothelial function, which can cause hypertension and thrombosis, is often seen in patients with coronary artery disease, diabetes mellitus, hypertension, hypercholesterolemia, and in smokers. Endothelial dysfunction is also correlated with future adverse cardiovascular events.
In blood vessels, vascular smooth muscle cells are behind the endothelial cells, the endothelial cells forming a thin layer between the blood and the muscle cells. Vascular smooth muscle contracts or relaxes to change both the diameter of blood vessels and, as a result, the local blood pressure. Arteries have more smooth muscle than veins, and so generally have greater thickness. Endothelial cells affect the movement of substances (such as nitric oxide) from the blood to the vascular smooth muscle cells which, in turn, dilate and contract the vessel. Proper functioning of the vascular endothelium and vascular smooth muscle cells, together, is important for fast end effective physiological response to stresses such as exercise.
Nitric oxide is an important signaling molecule involved in various physiological and pathological processes. Of particular relevance here, nitric oxide is a powerful vasodilator which has a very short half-life in the blood. Nitroglycerine and amyl nitrite, used to treat heart conditions, are precursors of nitric oxide.
The vascular endothelium could be considered the largest organ in the human body: the area inside the lungs alone can have a surface area of over 3,500 square feet, larger than a tennis court. Oxygen, carbon dioxide, and other important substances pass through the endothelium in the lungs, blood vessels, and elsewhere, making it important in regulating homeostasis. Hormones and other vasoactive substances affect the functioning of the endothelium. For example, the permeability of the vascular endothelium varies in response to oxygen levels, hormones, and other stimuli.
The endothelium has a variety of functions. Endothelium plays a role in controlling vascular tone—i.e. the degree of constriction or dilation. This, in turn, affects blood pressure and blood flow. It is a physiological barrier which regulates the flow of substances into and out of the vasculature. Some of these substances, in turn, affect vessel wall phenotype. Vascular endothelial cells also act as signal transducers between the blood and other cells (e.g. smooth muscle cells). Vascular endothelial cells are involved in fluid filtration and hormone trafficking. It is involved in the removal and biotransformation of many drugs. It participates in immune responses, such as by binding immune complexes and immunological blood components.
Alterations to endothelium has been found to be a precursor to other conditions. For example, changes to the endothelium have been identified as precursors of diabetes linked atherosclerosis.
The endothelium is regulated by vasoactive compounds such as angiotensin II, prostacyclin, thromboxane A2, nitric oxide (NO), and endothelins. It can also produce and release vasoactive compounds. It is also affected by the expression and activity of enzymes such as angiotensin converting enzyme, endothelin converting enzyme, nucleotidases, NO synthase, and lipoprotein lipase. Disease states, in turn, can affect the ability of these mediators to control the vasculature normally.
Vasodilation is a term for the widening of blood vessels. Vasodilation results from relaxation of smooth muscle cells in the vessel walls, particularly in the large veins, large arteries, and smaller arterioles. The opposite of vasodilation is vasoconstriction, i.e. the narrowing of blood vessels. When blood vessels dilate, blood flow increases due to a decrease in vascular resistance. This also typically decreases blood pressure. Vasodilation and vasoconstriction response may be intrinsic (due to local processes or stimuli) or extrinsic (due to circulating hormones or the nervous system). In some cases, vasodilation and constriction are systemic —i.e. occurring simultaneously throughout the circulatory system. Substances that cause vasodilation are called vasodilators. Vascular dilation decreases endothelial “resistance” to blood flow by opening a wider passage for the blood. Constriction, in turn, increases resistance by narrowing the passage.
Dr. Robert Furchgott (1916-2009) was a Nobel Prize-winning American biochemist who contributed to the identification of nitric oxide as a transient cellular signal in mammals. His publicly available Nobel Prize lecture publication outlines his work in this area and provides useful background. Endothelium-Derived Relaxing Factor: Discovery, Early Studies, and Identification as Nitric Oxide, Robert F. Furchgott, Dec. 8, 1998.
Aspects of the work leading to this invention have determined that observations of vascular endothelium in blood capillaries supplying the skin provide information regarding the vascular endothelium elsewhere, such as in the same individual's heart.
Reflected color can be measured using a spectrophotometer, which typically makes measurements in the visible light region of a given color sample. Spectrophotometry uses photometers that can measure a light beam's intensity as a function of its color or wavelength. If, for example, readings are made at 10 nanometer increments, the visible light range of 400-700 nm will yield 31 readings. These readings can be used to draw a reflectance curve illustrating how much light of each wavelength is reflected, as a function of wavelength.
Colorimeters are an alternative to spectrophotometers. Colorimeters typically make a limited number of wideband spectral energy readings along the visible spectrum by using filtered photodetectors.
The generic term “color detector” refers to spectrophotometers, colorimeters, and their functional equivalents which are capable of detecting and quantifying at least red wavelengths.
The Konica Minolta CM 700d spectrophotometer is a handheld unit that is capable of accurately quantifying the color of a surface. It is a large unit, however, that is not suitable to be worn like a wristwatch. U.S. Pat. No. 5,043,571, originally assigned to Minolta Camera KK, discloses a color CCD based spectrophotometer that is amenable to miniaturization, however.
Colors can be defined numerically, and differences between two colors can also be calculated and defined numerically. Several quantitative color systems exist, and can be adapted for use with this invention.
One available system is the L*a*b* color space or Hunter L/a/b color space, which can be visualized as a rectangular 3D coordinate system. L indicates lightness, a is the red/green coordinate, and b is the yellow/blue coordinate. L can have a value from 0 (black) to 100 (perfect reflection). The a and b axes have no numerical limits. Coordinate a is positive when red, and negative when green. Positive b is yellow, and negative b is blue. Colors can be described numerically using numerical values for L, a, and b. Differences between two colors can be quantified for each of the individual L/a/b values (ΔL, Δa, Δb). Overall differences between two colors can be derived numerically based on the three Δ values.
An alternative system, L*C*h color space, uses cylindrical instead of rectangular coordinates. In this system, L indicates lightness, C represents chroma, and h is the hue angle. Chroma and hue are calculated from the a and b coordinates of the L/a/b color space.
Patients with coronary artery blockages may have minimal symptoms and an normal electrocardiogram (ECG) while at rest. Cardiac stimulation may be necessary to identify irregularities. A cardiac “stress test” measures the body's ability to respond to external stress in a controlled clinical environment. The stress response is typically induced by exercise. The stress of exercise can also be approximated using pharmaceutical stimulation (e.g. dobutamine or adenosine) for patients who cannot easily perform physical exercises.
Cardiac stress tests compare the coronary circulation while the patient is at rest versus the same patient's circulation during maximum physical exertion. The purpose is to identify any abnormal blood flow to the myocardium (heart muscle tissue). This can in turn be a reflection of the overall physical condition of the patient. Stress tests can be used to diagnose coronary artery disease, and to assess patient prognosis after a heart attack.
Cardiac stress tests involve heart stimulation, either by exercise on a treadmill, arm ergometer, exercise bicycle, or with pharmacological stimulation. The stress test is traditionally conducted with the patient connected to an ECG, and in some cases also an imaging device such as an echocardiograph. An ECG shows heartbeat speed and rhythm (steady or irregular). It also detects the strength and timing of electrical signals as they pass through the heart. During a standard stress test, blood pressure is also checked. Patients may be asked to breathe into a tube during the test to monitor breathing and gas exchange. A standard stress test shows changes in heart electrical activity, and whether the heart is getting enough blood during exercise.
In imaging stress tests, pictures are also taken of the heart during exercise and recovery. Imaging stress tests can show how well blood is flowing in the heart, valve function, and how effectively the heart pumps blood when it beats. Imaging stress tests often use echocardiography (echo). Echocardiography uses sound waves to create a moving picture of the heart. A stress test echocardiogram can show areas of poor blood flow in the heart, dead heart muscle tissue, and areas of the heart muscle wall which are contracting poorly (e.g. due to heart attack damage or insufficient blood flow). Imaging stress tests using radioactive dye are also available. Imaging stress tests are generally considered better at identifying heart disease than non-imaging tests, but are more costly.
Over the course of a stress test the level of mechanical stress is progressively increased, such as by increasing exercise resistance and/or speed. The technician or attending physician monitors outward symptoms and blood pressure response. Exercise may continue until the patient indicates that they wish to stop, or until a “peak exercise” threshold is attained. In the widely used Bruce Protocol (see below), peak exercise is defined by patient heart rate. Specifically, by subtracting the patient's age from 220 and multiplying the result by 85%. ([220−Age (years)]*0.85=Peak Heart Rate (in beats per minute)). Patients in poor cardiovascular health will typically reach their peak exercise heart rate relatively quickly during exercise. Fit patients require more strenuous exercise to reach a given heart rate.
The Bruce protocol is a particular diagnostic stress test used in the evaluation of cardiac function, developed by Dr. Robert Bruce. A Bruce protocol stress test involves walking on a treadmill while the heart is monitored by an electrocardiograph with electrodes attached to the body. Ventilation volumes and respiratory gas exchanges are also monitored before, during, and after exercise. Treadmill speed and inclination are increased over the course of the test (e.g. every three minutes) until the patient signals that they need to stop. Typically, during a Bruce Protocol, heart rate and perceived exertion are taken every minute, and blood pressure is measured at the end of each stage (i.e. every three minutes).
Doctors commonly classify patient heart failure according to the severity of their symptoms. One common system is the New York Heart Association (NYHA) Functional Classification. It places patients in one of four categories based on how much they are limited in their physical activity. Class I: No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea (shortness of breath). Class II: Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea (shortness of breath). Class III: Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation, or dyspnea. Class IV: Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases.
Acetylcholine is believed to dilate normal blood vessels by promoting the release of a vasorelaxant substance from the endothelium (endothelium-derived relaxing factor). Paradoxical Vasoconstriction Induced by Acetylcholine in Atherosclerotic Coronary Arteries, P L Ludmer et al., N Engl J Med. 1986 Oct. 23; 315(17):1046-51. This article reports that in each of four normal coronary arteries, acetylcholine caused a dose-dependent dilation from a control diameter of 1.94+/−0.16 mm to 2.16+/−0.15 mm with the maximal acetylcholine dose (P less than 0.01). In contrast, all eight of the arteries with advanced stenosis showed dose-dependent constriction, from 1.05+/−0.05 to 0.32+/−0.16 mm at the highest concentration of acetylcholine (P less than 0.01), with temporary occlusion in five. Five of six vessels with minimal disease also constricted in response to acetylcholine. All vessels dilated in response to nitroglycerin, however. The study concluded that paradoxical vasoconstriction induced by acetylcholine occurs early as well as late in the course of coronary atherosclerosis. The findings suggested that abnormal vascular response to acetylcholine is indicative of a defect in endothelial vasodilator function, and may be important in the pathogenesis of coronary vasospasm. Related principles are understood to underlie the “wet run” protocol, described below.
Published Patent application US 2014/0378779 (Freeman et al.) discloses computer-based systems and techniques for analyzing skin coloration using spectral imaging to determine a medical condition of an individual. Freeman also teaches providing feedback to a rescuer or other medical professional based on the colorimetric properties of the patient's skin. Freeman Abstract and paragraph [0002].
Freeman discloses measuring skin color as quantified using an L/a/b color scale. Freeman FIG. 6, paragraphs [0093]-[0097], etc. It also teaches that a spectrophotometer can be used to monitor the color of patient skin surfaces, among other possible devices. Freeman [0085], [0097]. Obtaining the color information can include obtaining baseline colorimetric properties based on an intensity of light radiation reflected from the individual's skin, applying a stimulus configured to produce a change in the colorimetric properties of the individual's skin, and obtaining one or more additional measurements of the colorimetric properties at times selected to capture changes in the colorimetric properties of the individual's skin based on the applied stimulus.
U.S. Pat. No. 7,620,212 (Allen et al.) relates to electro-optical sensors for use in biometric analysis of optical spectra of tissue. Allen 1:52-1:56. Devices according to Allen can include a number of forms having a variety of functions. Allen largely focuses on using biometric methods to determine individual identities and/or demographic information such as age and sex. Allen also discloses using spectral data to determine physiological states of human patients based on spectral variation. Allen 4:17-4:21. Spectrometers can be used to detect spectroscopic changes in skin color to determine physiological states in patients. This functionality can be used as a stress detector or as a lie detector. Allen discloses that stress in humans can cause changes in skin color, such as reddening, which can be detected spectroscopically. The changes in skin color are believed to result from changes in blood flow in the tissue as a result of stress. Allen 18:14-18:40.
U.S. Pat. No. 5,671,735 (MacFarlane et al.) discloses a method and apparatus for determining the condition of a test subject using a color measuring instrument to detect changes in a color factor indicative of a condition such as a disease, aging, etc. For example, a medical condition such as hyperbilirubinemia that affects skin color can be detected. Color factors such as Hunter b and L can be measured for the subject's skin. For predetermined ranges of one color factor, in particular L, changes in the other color factor, e.g. Hunter b, above predetermined levels are indicative of the medical condition. Sequential color readings can indicate the presence or absence of a condition based upon changes in the measured color factor, or lack of changes, over time.
When a medical condition affecting skin color is detected in a procedure like that described for hyperbilirubinemia, the measuring of skin color characteristics preferably continues at regular intervals until the symptomatic color characteristic abates sufficiently to indicate the individual's recovery from the medical condition. In the case of hyperbilirubinemia, phototherapy is administered once a sufficient change in Hunter b is observed to indicate the jaundice symptomatic of hyperbilirubinemia. Throughout the course of phototherapy, the Hunter b and L color characteristics are continually monitored until the jaundice has been eliminated and treatment can be discontinued. MacFarlane 2:66-3:9.
U.S. Pat. No. 7,483,733 (Shani et al.) discloses a non-invasive method and apparatus to detect and monitor medical shock. A color sensor is used to detect skin color changes from pink to white (when the skin is depressed to expel blood) and then back to pink (as blood returns to capillaries when pressure is removed) in the relevant skin area. The time required for the skin to return to a pink color (i.e. CFT—capillary filling time) is determined. Slow recovery to an oxygenated pink color is indicative of shock.
U.S. Patent Application Publication 2016/0073886 (Connor) discloses wearable spectroscopic sensors for measuring food consumption. Connor FIG. 19 shows an example of a wearable device for the arm with a plurality of close-fitting biometric sensors.
U.S. Pat. No. 5,564,417 (Chance '417) teaches a wearable tissue spectrophotometer for in vivo examination of tissue of a specific target region. Chance '417 1:12-1:14. The spectrophotometer includes a phase detector for measuring a phase shift between the introduced and detected light, a magnitude detector for determination of light attenuation in the examined tissue, and a processor adapted to calculate the photon migration pathlength and determine a physiological property of the examined tissue based on the pathlength and on the attenuation data.
Chance '417 describes a path length corrected oximeter that utilizes principles of continuous wave spectroscopy and phase modulation spectroscopy. The oximeter is a compact unit constructed to be worn by a subject on the body over long periods of activity. The oximeter is also suitable for tissue monitoring in critical care facilities, in operating rooms while undergoing surgery, or in trauma related situations. The oximeter is mounted on a body-conformable support structure placed on the skin. Chance 1:52-1:61.
U.S. Pat. No. 5,402,778 (Chance '778) discloses a system for examination of a relatively small volume of biological tissue of interest using visible or infra-red radiation and a spectrophotometer. The spectrophotometer is a continuous wave spectrophotometer, a phase modulation spectrophotometer, or a time-resolved spectrophotometer. Chance '778 Abstract. In one example a human finger is inserted into a hollow cylinder, and the optical properties of the finger are measured by a spectrophotometer.
U.S. Pat. No. 8,082,015 (Yodh et al.) discloses a device, system, and method for determining the characteristics of deep tissue. Blood flow rate characteristics are measured as a function of light fluctuations caused by the tissue, while the oxygenation characteristics are measured as a function of transmission of light through the tissue with respect to the wavelength of light. The tissue characteristics may be measured during times of varying levels of exercise intensity. Yodh Abstract. The invention relates to methods and apparatus for measuring the flow of blood and oxygenation characteristics using diffuse optical spectroscopy. Yodh paragraph 1:18-1:21. Generally, the measurement techniques derive tissue optical properties, for example, hemoglobin concentration and blood oxygen saturation from diffuse reflection spectroscopy (DRS) measurements, and blood flow from diffuse correlation spectroscopy (DCS) measurements. Yodh 5:20-5:24.
The above references are incorporated by reference, and should be considered as resources to support and assist implementation of the invention except to the extent that any references may provide definitions which directly conflict with definitions herein.